scholarly journals Expression Analysis of PMP22/Gas3 in Premalignant and Malignant Pancreatic Lesions

2005 ◽  
Vol 53 (7) ◽  
pp. 885-893 ◽  
Author(s):  
Junsheng Li ◽  
Jörg Kleeff ◽  
Irene Esposito ◽  
Hany Kayed ◽  
Klaus Felix ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Transforming Growth Factor ◽  
Ductal Adenocarcinoma ◽  
Mrna Levels ◽  
Normal Pancreas ◽  
Structural Protein ◽  
Pancreatic Cancer Cells ◽  
Cystic Tumors

PMP22 is a structural protein of Schwann cells, but it also influences cell proliferation. In the present study, quantitative RT-PCR (QRT-PCR) and immunohistochemistry were used to determine PMP22 mRNA levels and to localize PMP22 in the normal pancreas ( n=20), chronic pancreatitis (CP) ( n=22), pancreatic ductal adenocarcinoma (PDAC) ( n=31), intraductal papillary mucinous neoplasms (IPMN) ( n=9), mucinous cystic tumors (MCN) ( n=4), and in a panel of PanIN lesions ( n=29). PMP22 mRNA levels were significantly higher in CP (3-fold) and PDAC (2.5-fold), compared to normal pancreatic tissues. PMP22 expression was restricted to nerves in the normal pancreas, while in CP and PDAC PMP22 was also expressed in PanIN lesions and in a small percentage of pancreatic cancer cells. PMP22 was weak to absent in the tumor cells of IPMNs and MCNs. PMP22 mRNA was present at different levels in cultured pancreatic cancer cells and up-regulated by transforming growth factor (TGF)-β1 in 2 of 8 of these cell lines. In conclusion, PMP22 expression is present in both CP and PDAC tissues. Its expression in PanIN lesions and some pancreatic cancer cells in vitro and in vivo suggests a role of PMP22 in the neoplastic transformation process from the normal pancreas to pre-malignant lesions to pancreatic cancer.

scholarly journals NR5A2 transcriptional activation by BRD4 promotes pancreatic cancer progression by upregulating GDF15

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Feng Guo ◽  
Yingke Zhou ◽  
Hui Guo ◽  
Dianyun Ren ◽  
Xin Jin ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Transcriptional Activation ◽  
Ductal Adenocarcinoma ◽  
Pancreatic Cancer Cells ◽  
Gene Sets ◽  
And Migration

AbstractNR5A2 is a transcription factor regulating the expression of various oncogenes. However, the role of NR5A2 and the specific regulatory mechanism of NR5A2 in pancreatic ductal adenocarcinoma (PDAC) are not thoroughly studied. In our study, Western blotting, real-time PCR, and immunohistochemistry were conducted to assess the expression levels of different molecules. Wound-healing, MTS, colony formation, and transwell assays were employed to evaluate the malignant potential of pancreatic cancer cells. We demonstrated that NR5A2 acted as a negative prognostic biomarker in PDAC. NR5A2 silencing inhibited the proliferation and migration abilities of pancreatic cancer cells in vitro and in vivo. While NR5A2 overexpression markedly promoted both events in vitro. We further identified that NR5A2 was transcriptionally upregulated by BRD4 in pancreatic cancer cells and this was confirmed by Chromatin immunoprecipitation (ChIP) and ChIP-qPCR. Besides, transcriptome RNA sequencing (RNA-Seq) was performed to explore the cancer-promoting effects of NR5A2, we found that GDF15 is a component of multiple down-regulated tumor-promoting gene sets after NR5A2 was silenced. Next, we showed that NR5A2 enhanced the malignancy of pancreatic cancer cells by inducing the transcription of GDF15. Collectively, our findings suggest that NR5A2 expression is induced by BRD4. In turn, NR5A2 activates the transcription of GDF15, promoting pancreatic cancer progression. Therefore, NR5A2 and GDF15 could be promising therapeutic targets in pancreatic cancer.

scholarly journals Upregulation of Mobility in Pancreatic Cancer Cells by Secreted S100A11 Through Activation of Surrounding Fibroblasts

2019 ◽  
Vol 27 (8) ◽  
pp. 945-956 ◽  
Author(s):  
Yosuke Mitsui ◽  
Nahoko Tomonobu ◽  
Masami Watanabe ◽  
Rie Kinoshita ◽  
I Wayan Sumardika ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cell Motility ◽  
Cancer Cells ◽  
Cellular Migration ◽  
Mitogen Activated Protein Kinase ◽  
Ductal Adenocarcinoma ◽  
Pancreatic Cancer Cells ◽  
Mechanistic Investigation

S100A11, a member of the S100 family of proteins, is actively secreted from pancreatic ductal adenocarcinoma (PDAC) cells. However, the role of the extracellular S100A11 in PDAC progression remains unclear. In the present study, we investigated the extracellular role of S100A11 in crosstalking between PDAC cells and surrounding fibroblasts in PDAC progression. An abundant S100A11 secreted from pancreatic cancer cells stimulated neighboring fibroblasts through receptor for advanced glycation end products (RAGE) upon S100A11 binding and was followed by not only an enhanced cancer cell motility in vitro but also an increased number of the PDAC-derived circulating tumor cells (CTCs) in vivo. Mechanistic investigation of RAGE downstream in fibroblasts revealed a novel contribution of a mitogen-activated protein kinase kinase kinase (MAPKKK), tumor progression locus 2 (TPL2), which is required for positive regulation of PDAC cell motility through induction of cyclooxygenase 2 (COX2) and its catalyzed production of prostaglandin E2 (PGE2), a strong chemoattractive fatty acid. The extracellularly released PGE2 from fibroblasts was required for the rise in cellular migration as well as infiltration of their adjacent PDAC cells in a coculture setting. Taken together, our data reveal a novel role of the secretory S100A11 in PDAC disseminative progression through activation of surrounding fibroblasts triggered by the S100A11‐RAGE‐TPL2‐COX2 pathway. The findings of this study will contribute to the establishment of a novel therapeutic antidote to PDACs that are difficult to treat by regulating cancer-associated fibroblasts (CAFs) through targeting the identified pathway.

scholarly journals DNA-Methylation-Caused Downregulation of miR-30 Contributes to the High Expression of XPO1 and the Aggressive Growth of Tumors in Pancreatic Ductal Adenocarcinoma

Cancers ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 1101 ◽  
Author(s):  
Asfar S. Azmi ◽  
Yiwei Li ◽  
Amro Aboukameel ◽  
Irfana Muqbil ◽  
Philip A. Philip ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Cancer Cells ◽  
Nuclear Export ◽  
The United States ◽  
High Expression ◽  
Ductal Adenocarcinoma ◽  
Multiple Tumor ◽  
Pancreatic Cancer Cells

Pancreatic ductal adenocarcinoma is one of the most aggressive cancers, with high mortality in the United States. One of the important signal transduction proteins involved in the regulation of pancreatic cancer’s aggressive progression is the nuclear export protein (XPO1). High expression of XPO1 has been found in pancreatic, lung, breast and other cancers and lymphomas with a poor prognosis of patients with tumors and high proliferative activity of cancer cells. Because XPO1 exports multiple tumor suppressor proteins simultaneously from the nucleus, the inhibition of XPO1 may retain multiple tumor suppressors in the nucleus, resulting in the suppression of cell proliferation and the induction of apoptosis in tumors. In this study, we found that the high expression of XPO1 in pancreatic cancer cells could be, in part, due to the methylation of the miR-30 gene, leading to the low expression level of the miR-30 family. By co-transfection of the XPO1 3′-UTR-Luc target vector with miR-30 mimic, we found that XPO1 is a direct target of the miR-30 family. We also observed that the enforced expression of the miR-30 family inhibited the expression of XPO1, resulting in the suppression of pancreatic cancer growth both in vitro and in vivo. These findings could help to design a novel therapeutic strategy for the treatment of pancreatic cancer by introducing miR-30 into cancer cells.

scholarly journals Targeted intervention of eIF4A1 inhibits EMT and metastasis of pancreatic cancer cells via c-MYC/miR-9 signaling

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Yuchong Zhao ◽  
Yun Wang ◽  
Wei Chen ◽  
Shuya Bai ◽  
Wang Peng ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
The Cancer Genome Atlas ◽  
Ductal Adenocarcinoma ◽  
Mesenchymal Transition ◽  
Early Metastasis ◽  
Pancreatic Cancer Cells ◽  
E Cadherin

Abstract Background Owing to the lack of effective treatment options, early metastasis remains the major cause of pancreatic ductal adenocarcinoma (PDAC) recurrence and mortality. However, the molecular mechanism of early metastasis is largely unknown. We characterized the function of eukaryotic translation initiation factors (eIFs) in epithelial-mesenchymal-transition (EMT) and metastasis in pancreatic cancer cells to investigate whether eIFs and downstream c-MYC affect EMT and metastasis by joint interference. Methods We used The Cancer Genome Atlas (TCGA) and Genome Tissue Expression (GTEx) databases to analyze eIF4A1 expression in PDAC tissues and further validated the findings with a microarray containing 53 PDAC samples. Expression regulation and pharmacological inhibition of eIF4A1 and c-MYC were performed to determine their role in migration, invasion, and metastasis in pancreatic cancer cells in vitro and in vivo. Results Elevated eIF4A1 expression was positively correlated with lymph node infiltration, tumor size, and indicated a poor prognosis. eIF4A1 decreased E-cadherin expression through the c-MYC/miR-9 axis. Loss of eIF4A1 and c-MYC decreased the EMT and metastasis capabilities of pancreatic cancer cells, whereas upregulation of eIF4A1 attenuated the inhibition of EMT and metastasis induced by c-MYC downregulation. Treatment with the eIF4A1 inhibitor rocaglamide (RocA) or the c-MYC inhibitor Mycro3 either alone or in combination significantly decreased the expression level of EMT markers in pancreatic cancer cells in vitro. However, the efficiency and safety of RocA alone were not inferior to those of the combination treatment in vivo. Conclusion Overexpression of eIF4A1 downregulated E-cadherin expression through the c-MYC/miR-9 axis, which promoted EMT and metastasis of pancreatic cancer cells. Despite the potential feedback loop between eIF4A1 and c-MYC, RocA monotherapy is a promising treatment inhibiting eIF4A1-induced PDAC metastasis.

scholarly journals DDX31: A Novel Functional Oncogene Promotes Migration and Proliferation of Pancreatic Cancer

2021 ◽  
Author(s):  
Yang Liu ◽  
Yongjie Xie ◽  
Jinsheng Ding ◽  
Liangliang Wu
Keyword(s):  
Pancreatic Cancer ◽  
Western Blot ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Cancer Cells ◽  
Blot Analysis ◽  
Western Blot Analysis ◽  
Ductal Adenocarcinoma ◽  
Rna Helicases ◽  
Pancreatic Cancer Cells

Abstract Purpose: Pancreatic cancer is one of the most malignant cancers with rapid disease progression. Pancreatic ductal adenocarcinoma (PDAC) accounts for more than 90% in exocrine pancreatic cancer. DDX31 is one of the Asp-Glu-Ala-Asp (DEAD)-box RNA helicases (DDX) family member, which has never been reported in pancreatic ductal adenocarcinoma. Through comprehensive analysis of bioinformatics screening, clinical pathological data and experiment results verification, we found DDX31 may be a promising oncogene.Patients and methods: The potential correlation between DDX3 expression and clinical feature of PDAC was analyzed, which revealed that patients with high DDX31 expression may have a poor prognosis. Elevated expression levels of DDX31 in PDAC compared with adjacent normal tissues were determined by immunohistochemical and Western blot analyses. Western blot analysis of N-cadherin, Snail, transwell, and wound healing assays was carried out to evaluate the pro-metastasis effects of DDX31 in PDAC. In vitro experiments included colony formation assay. Edu labeling assay, CCK-8, western blot analysis of Ki67, PCNA, and an in vivo subcutaneous mouse model were used to analyze the role of DDX31 in PDAC proliferation.Results: In our research, integrated bioinformatics analysis of the TCGA and GEO databases was performed to identify the metastasis and proliferation-related differentially expressed genes (DEG). DDX31 predicts strong metastasis and proliferation capacity of PDAC, was finally screened. Then, the clinical data identified that highexpression-DDX31 was correlated with pancreatic tumor size, pathological grade, and lymph node metastasis. The in vitro and vivo experiments revealed that overexpression-DDX31 promoted the migration, proliferation and cell viability of pancreatic cancer cells, these functions of DDX31 had also been proved in the knockdown results. Moreover, the EMT related markers and proliferation markers were identified to be positively regulated by DDX31 in pancreatic cancer cells.Conclusion: Thus, our work uncovered that DDX31 promotes migration and proliferation in PDAC and might be a promising therapeutic target in pancreatic cancer.

scholarly journals Kaempferol induces ROS-dependent apoptosis in pancreatic cancer cells via TGM2-mediated Akt/mTOR signaling

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Fengjiao Wang ◽  
Lai Wang ◽  
Chao Qu ◽  
Lianyu Chen ◽  
Yawen Geng ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Signaling Pathway ◽  
Colony Formation ◽  
Mtor Signaling ◽  
Mrna Levels ◽  
Apoptotic Signaling ◽  
Pancreatic Cancer Cells ◽  
Public Data

Abstract Background Kaempferol, a natural flavonoid, exhibits anticancer properties by scavenging reactive oxygen species (ROS). However, increasing evidence has demonstrated that, under certain conditions, kaempferol can inhibit tumor growth by upregulating ROS levels. In this study, we aimed to investigate whether kaempferol effectively suppresses pancreatic cancer through upregulation of ROS, and to explore the underlying molecular mechanism. Methods PANC-1 and Mia PaCa-2 cells were exposed to different concentrations of kaempferol. Cell proliferation and colony formation were evaluated by CCK-8 and colony formation assays. Flow cytometry was performed to assess the ROS levels and cell apoptosis. The mRNA sequencing and KEGG enrichment analysis were performed to identify differentially expressed genes and to reveal significantly enriched signaling pathways in response to kaempferol treatment. Based on biological analysis, we hypothesized that tissue transglutaminase (TGM2) gene was an essential target for kaempferol to induce ROS-related apoptosis in pancreatic cancer. TGM2 was overexpressed by lentivirus vector to verify the effect of TGM2 on the ROS-associated apoptotic signaling pathway. Western blot and qRT-PCR were used to determine the protein and mRNA levels, respectively. The prognostic value of TGM2 was analyzed by Gene Expression Profiling Interactive Analysis (GEPIA) tools based on public data from the TCGA database. Results Kaempferol effectively suppressed pancreatic cancer in vitro and in vivo. Kaempferol promoted apoptosis in vitro by increasing ROS generation, which was involved in Akt/mTOR signaling. TGM2 levels were significantly increased in PDAC tissues compared with normal tissues, and high TGM2 expression was positively correlated with poor prognosis in pancreatic cancer patients. Decreased TGM2 mRNA and protein levels were observed in the cells after treatment with kaempferol. Additionally, TGM2 overexpression downregulated ROS production and inhibited the abovementioned apoptotic signaling pathway. Conclusions Kaempferol induces ROS-dependent apoptosis in pancreatic cancer cells via TGM2-mediated Akt/mTOR signaling, and TGM2 may represent a promising prognostic biomarker for pancreatic cancer.

scholarly journals TGFβ Drives Metabolic Perturbations during Epithelial Mesenchymal Transition in Pancreatic Cancer: TGFβ Induced EMT in PDAC

Cancers ◽  
2021 ◽  
Vol 13 (24) ◽  
pp. 6204
Author(s):  
Meena U. Rajagopal ◽  
Shivani Bansal ◽  
Prabhjit Kaur ◽  
Shreyans K. Jain ◽  
Tatiana Altadil ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
High Resolution Mass Spectrometry ◽  
Ductal Adenocarcinoma ◽  
Resectable Pancreatic Cancer ◽  
Mesenchymal Transition ◽  
Pancreatic Cancer Cells

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy wherein a majority of patients present metastatic disease at diagnosis. Although the role of epithelial to mesenchymal transition (EMT), mediated by transforming growth factor beta (TGFβ), in imparting an aggressive phenotype to PDAC is well documented, the underlying biochemical pathway perturbations driving this behaviour have not been elucidated. We used high-resolution mass spectrometry (HRMS) based molecular phenotyping approach in order to delineate metabolic changes concomitant to TGFβ-induced EMT in pancreatic cancer cells. Strikingly, we observed robust changes in amino acid and energy metabolism that may contribute to tumor invasion and metastasis. Somewhat unexpectedly, TGFβ treatment resulted in an increase in intracellular levels of retinoic acid (RA) that in turn resulted in increased levels of extracellular matrix (ECM) proteins including fibronectin (FN) and collagen (COL1). These findings were further validated in plasma samples obtained from patients with resectable pancreatic cancer. Taken together, these observations provide novel insights into small molecule dysregulation that triggers a molecular cascade resulting in increased EMT-like changes in pancreatic cancer cells, a paradigm that can be potentially targeted for better clinical outcomes.

scholarly journals STAT1-mediated inhibition of FOXM1 enhances gemcitabine sensitivity in pancreatic cancer

2019 ◽  
Vol 133 (5) ◽  
pp. 645-663 ◽  
Author(s):  
Chao Liu ◽  
Jiaqi Shi ◽  
Qingwei Li ◽  
Zhiwei Li ◽  
Changjie Lou ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Immunohistochemical Analysis ◽  
Human Pancreatic Cancer ◽  
Ductal Adenocarcinoma ◽  
Luciferase Reporter ◽  
Pancreatic Cancer Cells ◽  
Foxm1 Expression

Abstract Forkhead box protein M1 (FOXM1) was identified as an oncogenic transcription factor and master regulator of tumor progression and metastasis. FOXM1 expression often correlates with poor prognosis and chemotherapy resistance. In the present study, we investigated the association of FOXM1 expression and chemoresistance in pancreatic cancer. Elevated FOXM1 protein levels were associated with gemcitabine chemoresistance in patients with pancreatic cancer. In gemcitabine resistance cell line models of pancreatic cancer, FOXM1 expression increased, which induced gemcitabine chemoresistance in vitro. In pancreatic cancer cells treated with gemcitabine, FOXM1 affected nuclear factor κB (NF-κB) signaling activity. Immunohistochemical analysis demonstrated a negative association of FOXM1 expression and the level of phosphorylated signal transducer and activator of transcription 1 (pSTAT1) in human pancreatic cancer tissues. Dual-luciferase reporter assays and chromatin-immunoprecipitation assays demonstrated that pSTAT1 directly binds to the FOXM1 promoter to down-regulate its transcription. Interferon γ (IFNγ) promoted gemcitabine-induced cell apoptosis and inhibited cell proliferation in vitro and in vivo by FOXM1 inhibition. These data suggested that FOXM1 enhances chemoresistance to gemcitabine in pancreatic cancer. IFNγ could be used to down-regulate the expression of FOXM1 through STAT1 phosphorylation, thereby increasing the sensitivity of pancreatic cancer cells to gemcitabine. These studies suggested the sensitization by IFNγ in pancreatic ductal adenocarcinoma (PDAC) chemotherapy, which requires further clinical studies.

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